DESCRIPTION: (Principal Investigator's) Transition metal-promoted higher order cycloaddition reactions are capable of generating structurally elaborate and stereochemically rich products that are often difficult or impossible to make in other ways. This proposal seeks to explore the scope and limitations of these transformations and to discover new synthetically useful examples. Higher-order cycloadditions in which one of the reactants possesses a heteroatom are rich sources of molecular structures amenable to conversion int pharmacologically active natural products. Representative examples of germacrane sesquiterpene lactones and aristotelia alkaloids that exhibit anticancer activities will be synthesized during the grant period using these methods. Efforts to make metal-promoted higher-order cycloaddition amenable to scale up will also be a focal point of the projected studies. Included in this portion of the investigation will be the development of catalytic versions of the reactions as well as modifications that would render the reactions more environmentally benign. Efforts to effect metal-promoted higher-order cycloadditions with resin-bound metals will also be pursued in the next grant cycle. Success in this endeavor could allow for convenient recycling of spent chromium(0) catalyst. Since most pharmacologically significant target molecule are chiral and non-racemic, substantial efforts directed toward developing asymmetric versions of these reactions will be pursued. The development of metal-mediated, multicomponent cycloadditions will be explored during the next grant period. In many instances these reactions can produce, in one operation, the entire polycyclic ring system of a number of natural product families, including both linear and angular triquinanes. The scope and limitations of several new cycloaddition processes discovered during the current grant period will be examined as well.